NO160920B - ANALOGY PROCEDURE TE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 2-PIPERAZINO-PTERIDINE DERIVATIVES. - Google Patents

Abstract

New therapeutically active 2-piperazino-pteridine derivatives with the general. formula. where. R 2 is a phenylalkylamino, alkylamino or dialkylamino group. a piperidino, morpholino, thiomorpholino or 1-oxydothiomorpholino group, R 2 is a dialkylamino, piperidino, morpholino, thiomorpholino or 1-oxydothiomorpholino group, and. R 2 is a halogen atom, an alkoxy, alkylthio, phenylalkoxy or phenylalkylthio group, the alkyl moiety in each case may contain from 1 to 3 carbon atoms. and their acid addition salts down inorganic or organic acids.The compounds have valuable pharmacological properties, especially anti-thrombotic and metastasis-inhibiting effects.Preparation of the compounds is described.

Description

In • US patent 2,940,972, tetrasubstituted pteridines are described which have valuable pharmacological properties, namely coronary dilating, sedative, antipyretic and analgesic effects.

It has now been found that the new 2-piperazino-pteridine derivs

with the .general formula

and their acid addition salts, especially their physiological

similar acid addition salts with inorganic or organic acids, likewise exhibit valuable pharmacological properties, surprisingly, however, anti-thrombotic and metastasis-inhibiting effects.

In the above general formula I means

R^ a phenylalkylamino-, dialkylamino-, piperidino-,

morpholino-, t'iomorpholino- or 1-oxido-

thiomorphic olino group,

R2 a dialkylamino-, piperidino-, morpholino-, thiomorpholino-

or 1-oxidothiomorpholino group, and

R^ a halogen atom, an alkoxy-, alkylthio-, phenylalkoxy-

or phenylalkylthio group, the alkyl part in each add-

trap may contain 1 to 3 carbon atoms.

The present invention thus relates to a method

for the preparation of the new 2-piperazino-pteridine derivatives of the above general formula I, their acid addition salts, in particular their physiologically compatible acid addition salts

ter with inorganic or organic acids.

A particularly preferred compound is 6-benzylthio-4,7-dimorpholino-2-piperazino-pteridine and its acid addition

salts, especially its physiologically compatible acid addition-

salts with inorganic or organic acids.

The new compounds are prepared according to the invention by the following methods: a) for the preparation of compounds of the general formula I where <]>R^ means a halogen atom: reaction of a compound of the general formula

where R^ and R2 are as indicated at the outset,

R^' means a halogen atom, and

Z 2 means a nucleophilic replaceable group such as a halogen atom, e.g. a chlorine or bromine atom,

with piperazine with the formula

The reaction is conveniently carried out in a solvent such as tetrahydrofuran, dioxane, benzene, toluene or dimethyl glycol ether, at temperatures between 50 and 150°C, preferably at the boiling temperature of the solvent used or in melt. It can be advantageous here to use an acid-binding agent such as sodium carbonate, triethylamine or pyridine. b) For the preparation of compounds of the general formula I, where R_3 means an alkoxy-, alkylmercapto-, phenylalkyloxy or phenylalkylmercapto group: reaction of a compound of the general formula where and R2 is as indicated at the beginning, and means a nucleophilic replaceable group so as a halogen atom, e.g. a chlorine or bromine atom, with a compound of the general formula

where R^' means an optionally substituted with a phenyl group, an alkoxy or alkyl mercapto group, the alkyl part in each case may contain 1 to 3 carbon atoms, or with its alkali salt.

The reaction is preferably carried out in a suitable solvent such as dioxane, tetrahydrofuran, methanol, ethanol, propanol, isopropanol or benzyl alcohol, and preferably in the presence of a suitable alkali salt of a compound of the general formula V, e.g. sodium methylate, sodium ethylate or sodium benzylmercaptide, suitably at temperatures between 50 and 150°C, e.g. at the boiling temperature of the solvent used.

The compounds prepared according to the invention can be transferred to their acid addition salts, in particular to their physiologically compatible salts with inorganic or organic acids. As acids come e.g. considering hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, lactic acid, citric acid, tartaric acid,

succinic acid, maleic acid or fumaric acid.

The compounds with the general formulas II, IV and V used as starting materials are mainly known or they can be prepared by the method described in US patent 2,940,972 (see examples A to C).

As mentioned at the outset, the new compounds of the general formula I and their physiologically compatible acid addition salts with inorganic or organic acids exhibit valuable pharmacological properties, in particular antithrombotic and metastasis-inhibiting effects and an inhibitory effect on phosphodiesterase.

For example, the connections were

A = 6-benzylthio-4,7-dimorpholino-2-piperazino-pteridine

B = 6-chloro-4,7-bis-(dimethylamino)-2-piperazino-pteridine

C = 6-benzylthio-4,7-bis-(dimethylamino)-2-piperazino-pteridine

D = 7-benzylamino-6-methylthio-4-(1-oxidothiomorpholino)-2-piperazino-pteridine and

E = 6-chloro-2-piperazino-4-dimethyl-amino-7-benzylamino-pteridine

examined for its inhibitory action on phosphodiesterase (PDE) from tumor cells and from human platelets in vitro according to the method described by von Poch et al, (see Naunyn-Schmiedeberg's Arch. Pharmak. 268, 272-279 (1971)) as follows :

a) Enzyme extraction:

Phosphodiesterase was recovered from mouse B16 melanoma tissue by centrifugation of the tissue homogenate at 5,000 x g (15 min, 4°C). Homogenization of the tissue was carried out by repeated freezing/thawing and homogenization according to Potter-Elvehjem resp. by ultrasound. The PDE-containing homogenate top layer was portionwise deep-frozen to -2<5>°C- Extraction of PDE from human platelets was carried out in an analogous manner by freezing/thawing and centrifugation. b) Determination of the PDE inhibition (PDE measurement): Determination of the PDE inhibition by means of the test compounds was carried out with a umol/1 3H-cAMP as substrate. The PDE inhibition was measured by measuring the degradation of an applied substrate <3>H-cAMP to <3>H-AMP compared to controls without test compound. The formed <3>H-AMP was separated from remaining <3>H-cAMP by means of a zinc sulfate-barium hydroxide precipitation.

The calculation of ED5q as the concentration that inhibited PDE activity by 50% was made by linear regression analysis.

Acute toxicity:1

The indicative acute toxicity of the test compounds was determined indicatively on groups of 5 mice each after oral administration of a single dose (observation time: 14 days):

The new compounds produced according to the invention are, due to their above-mentioned pharmacological properties, suitable for the prevention of thromboembolic disorders such as heart attack, cerebral infarction, so-called transient ischemic attack, Amaurosis fugax, for the prevention of arteriosclerosis and for the prevention of metastasis.

The dosage required to achieve an appropriate effect is suitably 0.1 to 4 mg/kg body weight, preferably 0.2 to 3 mg/kg body weight, 2 to 4 times a day.

The following examples will further illustrate the invention:

EXAMPLE A

2,6,7-trichloro-4-morpholino-pteridine

In a suspension of 13.5 g (0.05 mol) 2,4,6,7-tetrachloro-pteridine for approx. 400 ml of chloroform and 10 g (0.1 mol) of potassium bicarbonate, dissolved in 100 ml of water, are added slowly dropwise with vigorous stirring and cooling to -5 to 0°C a solution of 4.35 g (0.05 mol) morpholine in 100 ml chloroform, and then stirred for a further approx. 30 min. during cooling. The chloroform phase containing the reaction product is separated, dried over sodium sulphate and evaporated in vacuo.

Yield: 13.5 g (84% of the theoretical),

M.p.: 211-213°C (ethyl acetate).

Analogous to example A, the following compounds were prepared:

2,6,7-trichloro-4-thiomorpholino pteridine

m.p.: 191-193°C

2,6,7-trichloro-4-(1-oxidothiomorpholino)-pteridine m.p.: 212-214°C (decomp.)

EXAMPLE B

2,6-dichloro-4,7-bis-(1-oxidothiomorpholino)-pteridine 1 a solution of 13.5 g (0.05 mol) 2,4,6,7-tetrachloro-pteridine in 300 ml of dioxane is introduced slowly with stirring at room temperature, 23.8 g (0.2 mol) of thiomorpholine-1-oxide, dissolved in 100 ml of dioxane, whereby a yellowish precipitate quickly precipitates. The reaction mixture is absorbed for approx. 2 1 water. After a period of time, the secreted reaction product is suctioned off and washed with water and dried at approx. 70°C.

Yield: 19.2 g (88% of the theoretical),

M.p.: 237-239°C (ethanol).

Analogous to example B, the following compounds were prepared:

2,6-dichloro-4,7-dimorpholino-pteridine

m.p.: 206-208°C

2, 6-dichloro-4,7-bis-(thiomorpholino)-pteridine m.p.: 193-195°C (from dioxane)

2,6-dichloro-4,7-bis-(dimethylamino)-pteridine m.p.: 245-247°C

2,6-dichloro-4,7-dipiperidino-pteridine mp: 185-187°C.

EXAMPLE C

7-Benzylamino-2,6-dichloro-4-morpholino-pteridine

To a suspension of 9.6 g (0.03 mol) 2,6,7-trichloro-4-morpholino-pteridine in approx. A solution of 7 g (0.065 mol) benzylamine in 50 ml of dioxane is added to 150 ml of dioxane at room temperature slowly while stirring. After approx. After stirring for 1 hour, the reaction mixture is absorbed for approx. 1 liter of water. The precipitate that separates after settling is suctioned off, washed with water and

dried at 60°C.

Yield: 10.9 g (94% of the theoretical),

Melting point: 213-214°C (ethanol/dioxane = 2:1)

Analogous to example C, the following compounds were prepared: 7-benzylamino-2,6-dichloro-4-(1-oxidothiomorpholino)-pteridine m.p.: 253-254°C'

j

2,6-dichloro-7-morpholino-4-(1-oxidothiomorpholino)-pteridine m.p.: 215-217°C

2, 6-dichloro-4-morpholino-7-(1-oxidothiomorpholino)-pteridine m.p.: 218-220°C

EXAMPLE 1

6-chloro-4,7-dimorpholino-2-piperazino-pteridine

9.3 g (0.025 mol) of 2,6-dichloro-4,7-dimorpholino-pteridine are heated together with 8.6 g (0.1 mol) of anhydrous piperazine in 200 ml of dioxane for 1 hour under reflux. The solvent is largely distilled off, and the remaining residue is dissolved with approx. 100 ml of water. After a short period of time, vacuuming, washing with water and drying at approx. 70°C (m.p.: 218-220°C).

Yield: 8.9 g (85% of the theoretical),

M.p.: 220-222°C.

C18<H>25<C>1N8°2 (420'9)

EXAMPLE 2

6-Benzylthio-4,7-dimorpholino-2-piperazino-pteridine

A solution of 0.35 g sodium and 2 ml (approx. 0.017 mol) of benzyl mercaptan in 100 ml of dioxane, and then heated for approx. 2 hours under reflux cooling.

The solvent is largely distilled off in a vacuum, and the remaining residue is taken up in approx. 200 ml of water. After solidification, the reaction product is suctioned off, washed with water and dried at room temperature in a vacuum.

Yield: 6.4 g (84% of the theoretical).

After purification over a silica gel column (eluent: methanol/concentrated ammonia, 50:1) and recrystallization from ethyl acetate, the compound melts at 135-137°C.

<C>25H32N8°2S (508.7)

EXAMPLE 3

7-benzylamino-6-trimethoxy-4-(1-oxidothiomorph olino)-2-piperazino-pteridine

A solution of 0.23 g (0.01 mol ) sodium in 10 ml of methanol. The obtained mixture is heated for 30 minutes under reflux, and then the solvent is distilled off to a significant extent in vacuum. The residue is recorded for approx. 70 ml of water, and the secreted reaction product is suctioned off, washed with water and dried at approx. 60°C.

Yield: 2.6 g (93% of theoretical).

After reprecipitation from 0.1 n-hydrochloric acid using ammonia and recrystallization from ethyl acetate/methanol (4:1), the compound melts at 148-151°C.

C22<H>28<N>8°2<S> (468'6)

EXAMPLE 4

6-chloro-4-morpholino-7-(1-oxidothiomorpholino)-2-piperazino-pteridine

Prepared analogously to example 1 from 2,6-dichloro-4-morpholino-7-(1-oxidothiomorpholino)-pteridine and piperazine.

M.p.: 225-227°C (reprecipitation from 0.1 n-HCl using ammonia).

EXAMPLE 5

6-Chloro-4,7-bis-(1-oxidothiomorpholino)-2-piperazino-pteridine

Prepared analogously to example 1 from 2,6-dichloro-4,7-bis-(1-oxidothiomorpholino)-pteridine and piperazine.

Melting point: 200°C (decomp.).

EXAMPLE 6

6-chloro-4,7-dipiperidino-2-piperazino-pteridine

Prepared analogously to example 1 from 2,6-dichloro-4,7-dipiperidino-pteridine and piperazine.

Melting point: at approx. 200°C, decomp.

EXAMPLE 7

6-Chloro-4,7-bis-(dimethylamino)-2-piperazino-pteridine

Prepared analogously to example 1 from 2,6-dichloro-4,7-bis-(dimethylamino)-pteridine and piperazine.

M.p.: 130-134°C.

EXAMPLE 8

6-Chloro-2-piperazino-4,7-bis-(thiomorpholino)-pteridine

Prepared analogously to example 1 from 2,6-dichloro-4,7-bis-(thiomorpholino)-pteridine and piperazine.

M.p.: 194-196°C (ethyl acetate).

EXAMPLE 9

6-Chloro-7-morpholino-4-(1-oxidothiomorpholino)-2-piperazino-pteridine

Prepared analogously to example 1 from 2,6-dichloro-7-morpholino-4-(1-oxidothiomorpholino)-pteridine and piperazine.

Temp.: 24 0°C decomp.

EXAMPLE 10

7-Benzylamino-6-chloro-4-morpholino-2-piperazino-pteridine

Prepared analogously to example 1 from 7-benzylamino-2,6-dichloro-4-morpholino-pteridine and piperazine.

Mp.: 195-197°C (methanol/water).

EXAMPLE 11

7-benzylamino-6-chloro-4-(1-oxidothiomorpholino)-2-piperazino-pteridine

Prepared analogously to example 1 from 7-benzylamino-2,6-dichloro-4-(1-oxidothiomorpholino)-pteridine and piperazine.

Temp.: 200°C decomp.

EXAMPLE 12

6-Benzylthio-4,7-bis-(dimethylamino)-2-piperazino-pteridine

Prepared analogously to example 2 from 6-chloro-4,7-bis-(dimethylamino)-2-piperazino-pteridine and benzyl mercaptan.

M.p.: 150-152°C.

EXAMPLE 13

7- benzylamino-6-methylthio-4-(1-oxidothiomorpholino)-2-piperazino-pteridine

Prepared analogously to example 2 from 7-benzylamino-6-chloro-4-(1-oxidothiomorpholino)-2-pipwrazino-pteridine and methyl mercaptan.

Temp. for the hydrochloride: 159-162°C.

EXAMPLE 14

4-morpholino-7-(1-oxidothiomorpholino)-2-piperazino-6-propylthio-pteridine

Prepared analogously to example 2 from 6-chloro-4-morpholino-7-(1-oxidothiomorpholino)-2-piperazino-pteridine and propyl mercaptan. Melting point: 125-130°C.

EXAMPLE 15

7-benzylamino-6-benzylthio-4-(1-oxidothiomorpholino)-2-piperazino-pteridine

Prepared analogously to example 2 from 7-benzylamino-6-chloro-4-(1-oxidothiomorpholino)-2-piperazino-pteridine and benzyl mercaptan.

Melting point: 160°C (decomp.).

EXAMPLE 16

6-ethoxy-2-piperazino-4,7-bis-(thiomorpholino)-pteridine

Prepared analogously to example 3 from 6-chloro-2-piperazino-4, 7-bis-(thiomorpholino)-pteridine and ethanol.

M.p.: 147-151°C.

EXAMPLE 17

6-Benzyloxy-4,7-bis-(dimethylamino)-2-piperazino-pteridine

Prepared analogously to example 3 from 6-chloro-4,7-bis-(dimethylamino)-2-piperazino-pteridine and benzyl alcohol.

M.p.: 166-168°C.

EXAMPLE 18

6-Chloro-2-piperazino-4-dimethylamino-7-benzylamino-pteridine

Prepared analogously to example 1 from 2,6-dichloro-4-dimethyl-amino-7-benzylamino-pteridine and piperazine.

M.p.: 134-137°C.

EXAMPLE 19

6-chloro-2-piperazino-4-thiomorpholino-7-benzylamino-pteridine

Prepared analogously to example 1 from 2,6-dichloro-4-thiomorpholino-7-benzylamino-pteridine and piperazine.

Melting point: 160-165°C.

EXAMPLE 2 0

6-chloro-2-piperazino-4-thiomorpholino-7-dimethylamino-pteridine

Prepared analogously to example 1 from 2,6-dichloro-4-thiomorpholino-7-dimethylamino-pteridine and piperazine.

M.p.: 205-207°C.

EXAMPLE 21

7-Benzylamino-6-benzylthio-2-piperazino-4-thiomorpholino-..pteridine

Prepared analogously to example 2 from 7-benzylamino-6-chloro-2-piperazino-4-thiomorpholino-pteridine.

Melting point: from 70°C (sintering).

Claims (2)

1. Analogous process for the preparation of therapeutically active 2-piperazino-pteridine derivatives of the general formula where Ri is a phenylalkylamino or dialkylamino group, a piperidino, morpholino, thiomorpholino or 1-oxidothiomorph olino group, R 2 is a dialkylamino, piperidino, morpholino, thiomorpholino or 1-oxidothiomorpholino group ■, and R3 is a halogen atom, an alkoxy, alkylthio, phenylalkyloxy or phenylalkylthio group, the alkyl part in each case can contain from 1 to 3 carbon atoms, and their acid addition salts, in particular their physiologically compatible acid addition salts with inorganic or organic acids, characterized in that a) for the preparation of compounds of the general formula I where R3 means a halogen atom, a compound is reacted with the general formula where Ri and R2 are as indicated at the outset, R3' is a halogen atom, and Z 2 means a nucleophilic replaceable group such as a halogen atom, with piperazine having the formula or b) for the preparation of compounds of the general formula I where R 3 means an alkoxy, alkyl mercapto, phenyl alkoxy or phenyl alkyl mercapto group, a compound is reacted with the general formula where R 1 and R 2 are as initially indicated, and Z 3 is a nucleophilic replaceable group such as a halogen atom, with a compound of the general formula where R 3 ' is an optionally substituted with a phenyl group alkoxy or alkyl mercapto group, the alkyl part in each case may contain 1 to 3 carbon atoms, or with an alkali salt thereof, and optionally, a thus prepared compound of the general formula I is then transferred to its acid addition salt, in particular to its physiologically compatible acid addition salt with an inorganic or organic acid. 2. Process according to claim 1 for the production of 6-benzylthio-4,7-dimorpholino-2-piperazino-pteridine, characterized in that corresponding starting materials are used.